Alzheimer's disease (AD) is a devastating and common disorder of aging which involves selective loss of brain cells. Approximately 5% of all cases are inherited in an autosomal dominant fashion but the remainder of the cases are sporadic. Most AD patients have a widely distributed deficiency of cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial electron transport chain. Loss of activity of this key bioenergetic enzyme perturbs various aspects of normal cellular functioning including disordered learning and memory, inhibition of long term potentiation, disordered amyloid metabolism and production of excess highly toxic oxygen radicals. Discovery of the basis of the COX lesion will provide clues about early pathogenic events in AD. The COX lesion in AD arises from mutations in two mitochondrial genes encoding COX subunits. The biochemical and functional phenotype can be transferred into mitochondrial DNA deficient neuroblastoma cells thus proving the genetic origin of the lesion and providing a unique cellular model of AD in which specific consequences of the COX defect can be evaluated. This project will use this novel model system to investigate the impact of aging related degradation of the mitochondrial genome on bioenergetic function. The functional impact of AD related bioenergetic failure will be further evaluated. This system is unique in that it can be terminally differentiated thus providing an excellent model of bioenergetic failure in post-mitotic, neuron-like cell. Consequences of differentiation versus non-differentiation will be studied. This system will also be used to study the consequences of bioenergetic failure on amyloid, tau, and presenilin metabolism. This project will provided and characterize the basic model to be used by other components of the program. Over the course of this project we will gain further information about the specific genetics of sporadic AD, the cellular consequences of bioenergetic failure in AD, and define the utility of a new technique for the study of AD, and other similar neurodegenerative diseases.